Lipid Matters

An occasional series of notes on publications or other items dealing with lipid science from a variety of contributors.

23rd December 2024

Lipid Regulation of Adenlylyl Cyclase

Most, if not all. of us learned about the regulation of membrane-bound adenylate cyclases (often referred to as mACs) during our training and careers as scientists.Typically, we learned about the regulation of these enzymes by specific G-proteins which are themselves activated by specific membrane receptors (G-protein-coupled receptors (GPCRs)). Over time, it became clear that these enzymes are regulated by a variety of mechanisms, all of which are molecules present in the cytosol. In a recent study, Landau et al (eLife 2024;13:RP101483) have discovered the transmembrane domains of mACs respond to aliphatic lipid and anadamide to control mACs stimulated by Gsα.  The lipid signals enhance some mACs isoforms, while attenuating other isoforms. Using chimeric constructs of the various isoforms of mACs, they further showed that the hexahelical transmembrane domains of these enzymes serve as receptors for these signals. Their results open up and new, and rather novel regulatory mechanism of mACs that had been unrecognized and potentially very important.

Up to now the two hexahelical transmembrane domains of mACs were considered to fix the enzyme to membranes. Here, we show that the transmembrane domains serve in addition as signal receptors and transmitters of lipid signals that control Gsα-stimulated mAC activities. We identify aliphatic fatty acids and anandamide as receptor ligands of mAC isoforms 1–7 and 9. The ligands enhance (mAC isoforms 2, 3, 7, and 9) or attenuate (isoforms 1, 4, 5, and 6) Gsα-stimulated mAC activities in vitro and in vivo. Substitution of the stimulatory membrane receptor of mAC3 by the inhibitory receptor of mAC5 results in a ligand inhibited mAC5–mAC3 chimera. Thus, we discovered a new class of membrane receptors in which two signaling modalities are at a crossing, direct tonic lipid and indirect phasic GPCR–Gsα signaling regulating the biosynthesis of cAMP.


Dan M. Raben - The John Hopkins University School of Medicine, Baltimore, MD, USA

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